Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Deacetylation of tumor-suppressor MST1 in Hippo pathway induces its degradation through HBXIP-elevated HDAC6 in promotion of breast cancer growth

Oncogene volume 35, pages 4048–4057 (2016)Cite this article

Subjects

Abstract

Reduction or loss of tumor-suppressor mammalian STE20-like kinase 1 (MST1) in Hippo pathway contributes to the tumorigenesis. However, the mechanism leading to reduction of MST1 in cancers remains poorly understood. In this study, we explored the hypothesis that the oncoprotein hepatitis B X-interacting protein (HBXIP) is involved in the reduction of MST1 in breast cancer. Immunohistochemical analysis of tissue microarrays revealed that the expression of HBXIP was negatively associated with that of MST1 in 98 clinical breast tissue samples. Then we found that HBXIP could posttranslationally downregulate MST1 in breast cancer cells. Mechanistically, we identified that MST1 could be acetylated on its lysine 35 residue in the cells. Strikingly, the treatment with trichostatin A, an inhibitor of histone deacetylases (HDACs), markedly increased the levels of MST1 acetylation and protein in the cells. Interestingly, the oncoprotein HBXIP could significantly inhibit acetylation of MST1, resulting in the reduction of MST1 protein. Notably, we revealed that the HDAC6 could reduce the protein levels of MST1 through deacetylation modification of MST1 in the cells. Moreover, our data revealed that HBXIP upregulated HDAC6 at the levels of mRNA and protein by activating transcription factor nuclear factor-κB. Deacetylation of MST1 promoted the interaction of MST1 with HSC70 in the cells, resulting in a lysosome-dependent degradation of MST1 via chaperone-mediated autophagy (CMA). Functionally, the reduction of tumor-suppressor MST1 mediated by HBXIP promoted the growth of breast cancer cells in vitro and in vivo. Thus we conclude that the deacetylation of MST1 mediated by HBXIP-enhanced HDAC6 results in MST1 degradation in a CMA manner in promotion of breast cancer growth. Our finding provides new insights into the mechanism of tumor-suppressor MST1 reduction in breast cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Zhao B, Li L, Lei Q, Guan KL . The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev 2010; 24: 862–874.

    Article  CAS  Google Scholar 

  2. Pan D . The Hippo signaling pathway in development and cancer. Dev Cell 2010; 19: 491–505.

    Article  CAS  Google Scholar 

  3. Piccolo S, Dupont S, Cordenonsi M . The biology of YAP/TAZ: Hippo signaling and beyond. Physiol Rev 2014; 94: 1287–1312.

    Article  CAS  Google Scholar 

  4. Hong W, Guan KL . The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin Cell Dev Biol 2012; 23: 785–793.

    Article  CAS  Google Scholar 

  5. Li H, Wolfe A, Septer S, Edwards G, Zhong X, Abdulkarim AB et al. Deregulation of Hippo kinase signalling in human hepatic malignancies. Liver Int 2012; 32: 38–47.

    Article  Google Scholar 

  6. Wang P, Mao B, Luo W, Wei B, Jiang W, Liu D et al. The alteration of Hippo/YAP signaling in the development of hypertrophic cardiomyopathy. Basic Res Cardiol 2014; 109: 435.

    Article  Google Scholar 

  7. Steinmann K, Sandner A, Schagdarsurengin U, Dammann RH . Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma. Oncol Rep 2009; 22: 1519–1526.

    CAS  PubMed  Google Scholar 

  8. Minoo P, Zlobec I, Baker K, Tornillo L, Terracciano L, Jass JR et al. Prognostic significance of mammalian sterile 20-like kinase 1 in colorectal cancer. Mod Pathol 2007; 20: 331–338.

    Article  CAS  Google Scholar 

  9. Cinar B, Fang PK, Lutchman M, Di Vizio D, Adam RM, Pavlova N et al. The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1. EMBO J 2007; 26: 4523–4534.

    Article  CAS  Google Scholar 

  10. Cinar B, Collak FK, Lopez D, Akgul S, Mukhopadhyay NK, Kilicarslan M et al. MST1 is a multifunctional caspase-independent inhibitor of androgenic signaling. Cancer Res 2011; 71: 4303–4313.

    Article  CAS  Google Scholar 

  11. Lin X, Cai F, Li X, Kong X, Xu C, Zuo X et al. Prognostic significance of mammalian sterile 20-like kinase 1 in breast cancer. Tumour Biol 2013; 34: 3239–3243.

    Article  CAS  Google Scholar 

  12. Kuser-Abali G, Alptekin A, Cinar B . Overexpression of MYC and EZH2 cooperates to epigenetically silence MST1 expression. Epigenetics 2014; 9: 634–643.

    Article  CAS  Google Scholar 

  13. Seidel C, Schagdarsurengin U, Blumke K, Wurl P, Pfeifer GP, Hauptmann S et al. Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol Carcinog 2007; 46: 865–871.

    Article  CAS  Google Scholar 

  14. Li S, Ran Y, Zhang D, Chen J, Zhu D . MicroRNA-138 plays a role in hypoxic pulmonary vascular remodelling by targeting Mst1. Biochem J 2013; 452: 281–291.

    Article  CAS  Google Scholar 

  15. Li K, Wang R, Lozada E, Fan W, Orren DK, Luo J . Acetylation of WRN protein regulates its stability by inhibiting ubiquitination. PLoS One 2010; 5: e10341.

    Article  Google Scholar 

  16. Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell 2011; 42: 719–730.

    Article  CAS  Google Scholar 

  17. Zhao D, Zou SW, Liu Y, Zhou X, Mo Y, Wang P et al. Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell 2013; 23: 464–476.

    Article  CAS  Google Scholar 

  18. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB . Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003; 370: 737–749.

    Article  CAS  Google Scholar 

  19. Zhang L, Liu S, Liu N, Zhang Y, Liu M, Li D et al. Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity. Protein Cell 2014; 6: 42–54.

    Article  Google Scholar 

  20. Park SJ, Kim JK, Bae HJ, Eun JW, Shen Q, Kim HS et al. HDAC6 sustains growth stimulation by prolonging the activation of EGF receptor through the inhibition of rabaptin-5-mediated early endosome fusion in gastric cancer. Cancer Lett 2014; 354: 97–106.

    Article  CAS  Google Scholar 

  21. Saji S, Kawakami M, Hayashi S, Yoshida N, Hirose M, Horiguchi S et al. Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. Oncogene 2005; 24: 4531–4539.

    Article  CAS  Google Scholar 

  22. Aldana-Masangkay GI, Sakamoto KM . The role of HDAC6 in cancer. J Biomed Biotechnol 2011; 2011: 875824.

    Article  Google Scholar 

  23. Melegari M, Scaglioni PP, Wands JR . Cloning and characterization of a novel hepatitis B virus X binding protein that inhibits viral replication. J Virol 1998; 72: 1737–1743.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu F, You X, Wang Y, Liu Q, Liu Y, Zhang S et al. The oncoprotein HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF. Carcinogenesis 2014; 35: 1144–1153.

    Article  CAS  Google Scholar 

  25. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM . Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 2012; 150: 1196–1208.

    Article  CAS  Google Scholar 

  26. Hu N, Zhang J, Cui W, Kong G, Zhang S, Yue L et al. miR-520b regulates migration of breast cancer cells by targeting hepatitis B X-interacting protein and interleukin-8. J Biol Chem 2011; 286: 13714–13722.

    Article  CAS  Google Scholar 

  27. Liu S, Li L, Zhang Y, Zhao Y, You X, Lin Z et al. The oncoprotein HBXIP uses two pathways to up-regulate S100A4 in promotion of growth and migration of breast cancer cells. J Biol Chem 2012; 287: 30228–30239.

    Article  CAS  Google Scholar 

  28. Liu Q, Bai X, Li H, Zhang Y, Zhao Y, Zhang X et al. The oncoprotein HBXIP upregulates Lin28B via activating TF II D to promote proliferation of breast cancer cells. Int J Cancer 2013; 133: 1310–1322.

    Article  CAS  Google Scholar 

  29. Yue L, Li L, Liu F, Hu N, Zhang W, Bai X et al. The oncoprotein HBXIP activates transcriptional coregulatory protein LMO4 via Sp1 to promote proliferation of breast cancer cells. Carcinogenesis 2013; 34: 927–935.

    Article  CAS  Google Scholar 

  30. Zhao B, Ye X, Yu J, Li L, Li W, Li S et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 2008; 22: 1962–1971.

    Article  CAS  Google Scholar 

  31. Hsu YL, Hung JY, Chou SH, Huang MS, Tsai MJ, Lin YS et al. Angiomotin decreases lung cancer progression by sequestering oncogenic YAP/TAZ and decreasing Cyr61 expression. Oncogene 2015; 34: 4056–4068.

    Article  CAS  Google Scholar 

  32. Salah Z, Melino G, Aqeilan RI . Negative regulation of the Hippo pathway by E3 ubiquitin ligase ITCH is sufficient to promote tumorigenicity. Cancer Res 2011; 71: 2010–2020.

    Article  CAS  Google Scholar 

  33. Kang R, Tang D, Schapiro NE, Loux T, Livesey KM, Billiar TR et al. The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics. Oncogene 2014; 33: 567–577.

    Article  CAS  Google Scholar 

  34. Ge X, Jin Q, Zhang F, Yan T, Zhai Q . PCAF acetylates {beta}-catenin and improves its stability. Mol Biol Cell 2009; 20: 419–427.

    Article  CAS  Google Scholar 

  35. Perez-Mancera PA, Rust AG, van der Weyden L, Kristiansen G, Li A, Sarver AL et al. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. Nature 2012; 486: 266–270.

    Article  CAS  Google Scholar 

  36. Zhang Z, Yamashita H, Toyama T, Sugiura H, Omoto Y, Ando Y et al. HDAC6 expression is correlated with better survival in breast cancer. Clin Cancer Res 2004; 10: 6962–6968.

    Article  CAS  Google Scholar 

  37. Ding G, Liu HD, Huang Q, Liang HX, Ding ZH, Liao ZJ et al. HDAC6 promotes hepatocellular carcinoma progression by inhibiting P53 transcriptional activity. FEBS Lett 2013; 587: 880–886.

    Article  CAS  Google Scholar 

  38. Madonna R, Geng YJ, Bolli R, Rokosh G, Ferdinandy P, Patterson C et al. Co-activation of nuclear factor-kappaB and myocardin/serum response factor conveys the hypertrophy signal of high insulin levels in cardiac myoblasts. J Biol Chem 2014; 289: 19585–19598.

    Article  CAS  Google Scholar 

  39. Montagner M, Enzo E, Forcato M, Zanconato F, Parenti A, Rampazzo E et al. SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature 2012; 487: 380–384.

    Article  CAS  Google Scholar 

  40. Mizushima N, Levine B, Cuervo AM, Klionsky DJ . Autophagy fights disease through cellular self-digestion. Nature 2008; 451: 1069–1075.

    Article  CAS  Google Scholar 

  41. Jeong H, Then F, Melia Jr TJ, Mazzulli JR, Cui L, Savas JN et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 2009; 137: 60–72.

    Article  CAS  Google Scholar 

  42. Cuervo AM, Knecht E, Terlecky SR, Dice JF . Activation of a selective pathway of lysosomal proteolysis in rat liver by prolonged starvation. Am J Physiol 1995; 269: C1200–C1208.

    Article  CAS  Google Scholar 

  43. Majeski AE, Dice JF . Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol 2004; 36: 2435–2444.

    Article  CAS  Google Scholar 

  44. Lin CW, Chang YL, Chang YC, Lin JC, Chen CC, Pan SH et al. MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1. Nat Commun 2013; 4: 1877.

    Article  Google Scholar 

  45. Harvey KF, Zhang X, Thomas DM . The Hippo pathway and human cancer. Nat Rev Cancer 2013; 13: 246–257.

    Article  CAS  Google Scholar 

  46. Wang FZ, Sha L, Zhang WY, Wu LY, Qiao L, Li N et al. Involvement of hepatitis B X-interacting protein (HBXIP) in proliferation regulation of cells. Acta Pharmacol Sin 2007; 28: 431–438.

    Article  Google Scholar 

  47. Rausa FM 3rd, Hughes DE, Costa RH . Stability of the hepatocyte nuclear factor 6 transcription factor requires acetylation by the CREB-binding protein coactivator. J Biol Chem 2004; 279: 43070–43076.

    Article  CAS  Google Scholar 

  48. Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q et al. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell 2011; 43: 33–44.

    Article  CAS  Google Scholar 

  49. Ropero S, Esteller M . The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 2007; 1: 19–25.

    Article  CAS  Google Scholar 

  50. Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 2012; 150: 780–791.

    Article  CAS  Google Scholar 

  51. Ren A, Yan G, You B, Sun J . Down-regulation of mammalian sterile 20-like kinase 1 by heat shock protein 70 mediates cisplatin resistance in prostate cancer cells. Cancer Res 2008; 68: 2266–2274.

    Article  CAS  Google Scholar 

  52. Li H, Liu Q, Wang Z, Fang R, Shen Y, Cai X et al. The oncoprotein HBXIP modulates the feedback loop of MDM2/p53 to enhance the growth of breast cancer. J Biol Chem 2015; 290: 22649–22661.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Basic Research Program of China (973 Program, No. 2015CB553905), the National Natural Scientific Foundation of China (Nos. 81372186, 81272218, 31470756) and Tianjin Natural Scientific Foundation (No. 14JCZDJC32800).

Author information

Author notes

  1. L Li and R Fang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China

    L Li, R Fang, B Liu, H Shi, Y Wang, W Zhang & L Ye

  2. Department of Cancer Research, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China

    X Zhang

Authors
  1. L Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. X Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to X Zhang or L Ye.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, L., Fang, R., Liu, B. et al. Deacetylation of tumor-suppressor MST1 in Hippo pathway induces its degradation through HBXIP-elevated HDAC6 in promotion of breast cancer growth. Oncogene 35, 4048–4057 (2016). https://doi.org/10.1038/onc.2015.476

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.476

This article is cited by

Search

Advanced search

Quick links